Bioavailability & Bioequivalence

Pharmacokinetic Principles
 Bioavailability and Its Assessment
• Bioavailability: The rate and extent to which the parent
compound reaches the general circulation.

• Absolute Bioavailability

• requires I.V. administration

• Ratio of the oral: intravenous AUC values normalized for dose
• Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)

• Relative Bioavailability

• no I.V. reference
• comparison AUC values (ratio) of different dosage forms / formulations
• Frel = (AUC a / AUC b) * (Dose b /Dose a)
Area Under the Concentration – Time
Curve (AUC)
 A quantitative measure for
exposure from dosing time to
time ‘t’
 An important parameter in PK
 AUC(t) and AUC(inf)
 Determined by trapezoidal
method
 AUC(inf) = AUC(t) + Ct/k
Units: Conc*t (mg/L * h)
 Proportional to Dose (linear
PK)
 Accuracy of the estimate
depends on frequency of
sampling
Plasma Concentration-Time Profile for a
Drug Following a Single Oral Dose

• Rate of drug accumulation at

any time:
• dDBODY/dt= dDABS/dt -
dDELIM/dt

• Absorption Phase:
• dDABS/dt > dDELIM/dt

• At time of peak drug conc.:

• dDABS/dt = dDELIM/dt

• Post-absorption Phase:
• dDABS/dt < dDELIM/dt
Comparison of the Rates of Drug
Absorption
Effect of a Change in Absorption Rate
Constant (Ka) on Plasma Drug
Concentration Versus Time Curve

0.5/hr

0.2/hr
 Pharmacokinetic Assessment of
Absorption Interactions
• Clinically significant interactions are typically
assessed in terms of:

• Rate of Absorption:
– peak plasma drug concentrations (Cmax)
– time to Cmax (tmax)

• Extent of Absorption:
– area under the concentration-time curve (AUC)
 Bioequivalence
Definition
It is the absence of significance difference in the rate
and extent to which active ingredient or active moiety
in pharmaceutical equivalent or pharmaceutical
alternative becomes available at the site of drug
action when administered at the same molar dose
under similar conditions in an appropriately
designed study
Regulatory Requirements for BE

Evaluation of Quality and

interchangeability of Medicinal
Products
 Regulatory Requirements
for BE
 FDA - Guidance for Industry: “Bioavailability and
Bioequivalence Studies for Orally Administered Drug
Products .
 WHO – Multisource (generic) pharmaceutical products:
Guidelines on registration requirements to establish
interchangeability
 CN – Guidance for Industry; Conduct and analysis of
bioavailability and bioequivalence studies – Part A: Oral
dosage formulations used for systemic effects
• ICH Guidelines
• Development Safety Update Report;
•         Structure and Content of Clinical Study Reports;
       Good Clinical Practice;
•        General Considerations for Clinical Trials;
•        Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting;
•        Statistical Principles for Clinical Trials;
•        Validation of Analytical Procedures – Text and
Methodology;
•       Test Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products – Chemical
Substances;
 India (CDSCO):
Central Drugs Standard Control Organization
     Bioavailability / Bioequivalence:
      Requirements and Guidelines for Permission to Import and / or
Manufacture of New Drugs for Sale or
to Undertake Clinical Trials:
       Submission of Clinical Trial Application for Evaluating Safety and Efficacy:
        Ethical Guidelines for Biomedical Research on Human Participants
Regulatory Requirements for BE
 Bioequivalence Studies

 in vivo comparison of products by means of

volunteers serving as “in-vivo dissolution model”
 ‘biological quality control’

comparison of product characteristics in order to

ensure therapeutic equivalence
 Immediate and Modified Release
Dosage Forms
BE is generally required and can be
investigated by means of

♦ pharmacokinetic (BE) studies (preferred as

most sensitive)
♦ comparative pharmacodynamic studies
♦ comparative clinical trials
♦ comparative in vitro trials
Immediate Release (IR) Dosage Forms

 possible BE exemptions

♦ aqueous solution (incl. syrups, elixirs, but no

suspensions)
♦ gases
♦ aqueous optic or ophthalmic products (contg. the same
actives and excipients)
♦ nebulizer inhalation products or nasal sprays (contg.
the same actives and excipients)
Bioequivalence for Immediate Release
Dosage Forms
 …the ‘parent’ drug substance within a single
dose 2-period crossover design is usually
appropriate
♦ dose- or time-dependent kinetics
♦ specific food recommendations in the SPC
♦ active metabolites
♦ pro-drugs
♦ enantiomers……
 Modified Release (MR) Dosage
Forms
 controlled (extended, sustained) release
 delayed release
♦ single unit formulations
♦ multiple unit formulations
♦ single dose study (fasting)
♦ multiple dose study (steady state conditions)
♦ food-effect study (“dose-dumping” under
high-fat conditions;)
 Product strengths
♦ bioequivalence proven for one strength
♦ same manufacturer and manufacturing
process
♦ linear drug input
♦ same qualitative composition of different
strengths (WHO)
♦ same ratio between active substance and
excipients, or same excipients in case of low
concentration (less than 5 % API)
♦ similar in vitro dissolution (WHO)
 Bioequivalence for transdermal
therapeutic systems (TTS)

 BE by means of single and multiple dose

studies
 performing a replicate design study is
advisable (investigation of subject by formulation interaction)
 ‘BE’ regarding local tolerability
 dose proportionality issue: thorough in vitro
release testing and exact proportionality (partial
effective surface area!)
Bioequivalence for topical dosage forms
without systemic action

usually therapeutic studies necessary

(therapeutic equivalence, safety and tolerability usually
not possible by means of blood sampling and PK data)
 usually therapeutic studies necessary
(specific FDA guidance for corticosteroids…..)
 possibilities are e.g. skin stripping, micro dialysis
 inhalatives… metered dose
inhalers…(locally acting)
♦ usually therapeutic studies necessary
♦ in some cases PK studies for safety reasons
♦ in some cases PK studies in addition to in-
vitro (‚quality‘ - deposition characteristics e.g.
FPD)
♦ usually in patients